Hypertension is the second leading primary cause of end-stage renal disease;however, considerable variation exists with respect to the relative risk of hypertensive-induced renal damage in the veteran population. The factors that alter the susceptibility to hypertensive renal injury as well as the underlying mechanisms remain poorly understood. One of the difficulties in investigating the mechanisms that contribute to hypertensive renal injury is the wide spectrum of pathology observed in hypertensive patients with kidney damage. The two major pathophysiologic mechanisms thought to contribute to the pathogenesis and progression of hypertensive renal injury include local exposure to excessive pressures with resulting barotrauma and chronic ischemia with resulting hypoxia. While both mechanisms will contribute to the progression of renal injury, the relative contribution of barotrauma and ischemia to the observed injury likely differs among hypertensive individuals depending on the underlying pathophysiologic context and the presence of additional genetic or environmental risk factors. One such risk factor that is thought to alter the susceptibility to hypertensive renal injury is endothelial dysfunction with reduced levels of nitric oxide (NO). Reduced NO levels have been reported in human populations susceptible to an accelerated progression of hypertensive renal injury, such as African- Americans and individuals with chronic kidney disease. Yet, the role of NO availability on the relative contribution of BP dependent and independent pathways of renal injury, its effects on pathways of barotrauma vs. ischemia induced injury, and the underlying mechanisms remain poorly understood. In the studies proposed in this career development application, we will utilize groups of rats and mice with differences in NO availability as a broad model system to investigate the mechanisms by which reduced NO levels alter the susceptibility to hypertensive injury. We will perform these studies in two models of hypertension in which the pathogenesis of renal injury is thought to be predominantly mediated via barotrauma vs. ischemia pathways. These studies are of clinical significance and should lead to very novel insights regarding the mechanisms by which NO availability alters the susceptibility barotrauma and ischemia mediated pathways of renal injury during the pathogenesis and progression of hypertension. Studies in Aim 1 will focus on the temporal evolution of renal injury, several indices of NO availability, oxidative stress, and purported cellular mediators of injury (i.e., hypoxia, osteopontin, etc.). Dietary interventions will be used to alter the level of NO availability to determine the importance of NO in ameliorating renal injury in various hypertensive states. Studies in Aim 2 are focused on the potential BP dependent and independent mechanisms by which reduced NO availability may enhance the susceptibility to hypertensive renal injury. These studies will focus on the pressor and nonpressor effects of NO availability on the regulation of renal hemodynamics, renal function, and renal oxygenation levels during the pathogenesis and progression of hypertensive renal injury. The studies in Aim 3 will investigate the relative contribution of endothelial dependent and independent pathways in isolated mesenteric arteries to improve our understanding of the mechanisms contributing to the differences in NO availability between the experimental animals. In addition to the novel and clinically relevant set of research experiments, there are numerous informal and formal training activities that should prepare the applicant for an independent career in academic medicine. Furthermore, the proposed studies should also lead to several novel and relevant areas of research, which are independent of his mentoring group, which the applicant can pursue for independent funding. PUBLIC HEALTH RELEVANCE: Hypertension is the second leading cause of kidney failure. Some hypertensive populations, such as individuals of African-American heritage or those with underlying chronic kidney disease, have a much greater risk of progressing to kidney failure. This pattern is also observed in the veteran population. The goal of this project is to determine the potential mechanisms by which some risk factors, commonly found in individuals who are prone to develop chronic kidney disease, increase the susceptibility to hypertensive injury. These studies may lead to new treatments for the prevention of chronic kidney disease in the veteran population.